1. Field of the Disclosure
The present invention relates generally to certain Helicobacter pylori genetic regions, to the proteins expressed by these regions, and to the use of these genes and proteins for diagnostic and vaccine applications.
2. Brief Description of Related Art
Helicobacter pylori is a curved, microaerophilic, gram negative bacterium that has been isolated for the first time in 1982 from stomach biopsies of patients with chronic gastritis, Warren et al., Lancet i: 1273-75 (1983). Originally named Campylobacter pylori, it has been recognized to be part of a separate genus named Helicobacter, Goodwin et al., Int. J. Syst. Bacteriol. 39: 397-405 (1989). The bacterium colonizes the human gastric mucosa, and infection can persist for decades. During the last few years, the presence of the bacterium has been associated with chronic gastritis type B, a condition that may remain asymptomatic in most infected persons but increases considerably the risk of peptic ulcer and gastric adenocarcinoma. The most recent studies strongly suggest that H. pylori infection may be either a cause or a cofactor of type B gastritis, peptic ulcers, and gastric tumors, see e.g., Blaser, Gastroenterology 93: 371-83 (1987); Dooley et al., New Engl. J. Med. 321: 1562-66 (1989); Parsonnet et al., New Engl. J. Med. 325: 1127-31 (1991). H. pylori is believed to be transmitted by the oral route, Thomas et al., Lancet i: 340, 1194 (1992), and the risk of infection increases with age, Graham et al., Gastroenterology 100: 1495-1501 (1991), and is facilitated by crowding, Drumm et al., New Engl. J. Med. 4322: 359-63 (1990); Blaser, Clin. Infect. Dis. 15: 386-93 (1992). In developed countries, the presence of antibodies against H. pylori antigens increases from less than 20% to over 50% in people 30 and 60 years old respectively, Jones et al., Med. Microbio. 22: 57-62 (1986); Morris et al., N. Z. Med. J. 99: 657-59 (1986), while in developing countries over 80% of the population are already infected by the age of 20, Graham et al., Digestive Diseases and Sciences 36: 1084-88 (1991).
H. pylori factors that have been identified so far include the flagella that are probably necessary to move across the mucus layer, see e.g., Leying et al., Mol. Microbiol. 6: 2863-74 (1992); the urease that is necessary to neutralize the acidic environment of the stomach and to allow initial colonization, see e.g., Cussac et al., J. Bacteriol. 174: 2466-73 (1992), Perez-Perez et al., J. Infect. Immun. 60: 3658-3663 (1992), Austin et al., J. Bacteriol. 174: 7470-73 (1992), PCT Publ. No. WO 90/04030; the H. pylori cytotoxin (sometimes referred to as VacA, as it causes vacuolation), see e.g., PCT Publ. No. WO 93/18150, Telford, J. L. et al., J. Exp. Med. 179: 1653-58 (1994), Cover et al., J. Bio. Chem. 267: 10570-75 (1992), Cover et al., J. Clin. Invest. 90: 913-18 (1992), Leunk, Rev. Infect. Dis. 13: 5686-89 (1991); the H. pylori heat shock protein, see e.g., PCT Publ. No. WO 93/18150, Evans et al., Infect. Immun. 60: 2125-27 (1992), Dunn et al., Infect. Immun. 60: 1946-51 (1992), Austin et al., J. Bacteriol. 174: 7470-73 (1992); and the cytotoxin-associated protein, CagA, see e.g., PCT Publ. No. WO 93/18150, Covacci, A., et al., Proc. Natl. Acad. Sci. USA 90: 5791-95 (1993), Tummuru, M. K. et al., Infect. Immun. 61: 1799-1809 (1994).
Currently, H. pylori strains can be partitioned into at least two major groups, which either express (Type I) or do not express (Type II) the cytotoxin and the CagA proteins. Type I strains contain the CagA and toxin genes and produce active forms of these antigens. Type II strains lack the CagA locus and fail to express the cytotoxin. The association between the presence of the CagA gene and cytotoxicity suggests that the product of the CagA gene is necessary for the transcription, folding, export or function of the cytotoxin. Epidemiological analysis indicate that Type I bacteria are associated with duodenal ulcerations, gastric ulceration and sever forms of active gastritis.
For a general review of the pathogenic role of H. pylori in peptic ulcer, see Telford, J. L., et al., TibTech 12: 420-426 (1994).